Identification of flavonoids from natural products against hyperlipidaemia through computational approaches

Abstract

Over the centuries, hyperlipidaemia has been recognised as a major risk factor contributing to cardiovascular disease (CVD). Current research increasingly explores natural compounds such as flavonoids for their potential lipid-lowering effects. This study evaluated pharmacological potential of flavonoids to identify strong inhibitors for target receptor, Proprotein Convertase Subtilisin/Kexin Type.

Introduction

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide and continues to pose a major public health challenge. CVD encompasses a group of disorders affecting the heart and blood vessels, including coronary artery disease, cerebrovascular disease, and peripheral arterial disease.

Materials and methods

This study employed a four-stage computational approach involving ligand preparation and toxicity screening, protein structure refinement and validation, molecular docking, molecular dynamics (MD) simulation and MM/PBSA binding free-energy analysis. A systematic workflow was implemented to identify potential PCSK9 inhibitors

Ligand preparation.

Twenty-nine compounds comprising twenty-eight naturally occurring flavonoids and one FDA-approved drug (Simvastatin) used as the reference control were selected based on an extensive literature revi. Two-dimensional (2D) chemical structures were retrieved from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) in SDF format.

Refinement of PCSK9.

The three-dimensional structure of human proprotein convertase subtilisin/kexin type 9 (PCSK9) was refined using the SWISS-MODEL server (https://swissmodel.expasy.org/) [34]. The experimentally determined high-resolution crystal structure of human PCSK9 (PDB ID: 5OCA) was selected

Results

A summary of the findings is presented . The workflow illustrated the screening of 29 compounds through four sequential steps: toxicity screening, structure refinement, molecular docking and molecular dynamics simulation. Drug-likeness of 29 compound (28 flavonoids and one FDA-approved drug) were evaluated using SwissADME. Based on Lipinski’s Rule of Five, 24 compounds met all criteria as shown indicating favourable molecular properties.

Conclusion

In conclusion, this study systematically evaluated the potential of naturally occurring flavonoids as PCSK9 inhibitors using an integrated computational workflow. Of the 29 compounds initially screened, 24 compounds satisfied the drug-likeness and ADME criteria and demonstrated acceptable predicted toxicity profiles, supporting their suitability for further investigation. Based on molecular docking, seven flavonoids

Citation: Mustaffar Kamal NH, Ismail NA, Ali EZ (2026) Identification of flavonoids from natural products against hyperlipidaemia through computational approaches. PLoS One 21(10): e0346073. https://doi.org/10.1371/journal.pone.0346073

Editor: Jorddy Neves Cruz, Universidade Federal do Para, BRAZIL

Received: March 13, 2026; Accepted: September 16, 2026; Published: October 9, 2026

Copyright: © 2026 Mustaffar Kamal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information file.

Funding: The publication of this manuscript was supported by School of Graduate Studies (SGS), Management and Science University, SG-018-022020-SGS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.